General and Modular Route to (Halo)alkyl BCP-Heteroaryls Enabled by α‑Aminoalkyl Radical-Mediated Halogen-Atom Transfer

Synthesis of bicyclo[1.1.1]­pentane (BCP) heteroaryls continues to be a part of the most important tasks in organic synthesis because they are a significant class of bioisosteres with universal applications in drug discovery. However, the substrate scope of current multicomponent reactions is limited to tertiary alkyl radicals and prefunctionalized (het)­arenes due to their intrinsic mechanisms, resulting in a decrease in the application value. Herein, we report a straightforward alternative for the synthesis of (halo)­alkyl BCP-heteroaryls from [1.1.1]­propellane enabled by α-aminoalkyl radical-mediated halogen-atom transfer (XAT). Carbon radicals derived from commonly available precursors such as primary, secondary, and tertiary alkyl halides and polyhalides perform additions onto [1.1.1]­propellane to give BCP radicals, which then engage in C–H/C–C couplings with different heteroarenes. A wide range of (halo)­alkyl BCP-heteroaryls is easily constructed in moderate-to-good yields. Late-stage functionalization performed on approved drug derivatives proceeds with good efficiency to produce the corresponding BCP-heteroaryls. The control experiments and density functional theory (DFT) calculations reveal the radical nature of the multicomponent reaction. This approach not only verifies the application of the halogen-atom transfer (XAT) strategy but also provides a practical and efficient route to multifunctionalized BCPs, which significantly expands the range of BCP-heteroaryl-type bioisosteres for applications in drug development.